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Abstract

Peripheral neuropathy (PN) is one of the most common side effects of bortezomib therapy.
The majority of bortezomib-related PN is a sensory neuropathy of mild to moderate
degree, and is reversible after dose reduction or discontinuation. However, occasionally
bortezomib-induced neuropathy can be severe and affects motor and/or autonomic nerves,
and may be mediated by immune process. The role of immune modulation therapy in the
management of bortezomib-induced PN was not well established. Here, we reported a
case of bortezomib-induced severe PN that responded well to plasma exchange and steroid
treatment.

Keywords:

Background

Bortezomib is a reversible proteasome inhibitor, and has been approved by the FDA
for the treatment of multiple myeloma either in combination with other agents or as
a single agent [1,2]. One of the common side effects associated with bortezomib therapy is PN [3-7]. The neuropathy may be caused by direct toxic effect of bortezomib or through an
immunologically mediated process [3-7]. Here, we reported our experience in managing a severe bortezomib-related PN with
immune modulation treatment.

Case presentation

This patient is a 65 years old Caucasian male who was diagnosed with multiple myeloma
in December 2010 based on an IgG kappa paraprotein (3 g/dl), 25% kappa light chain
restricted- plasma cells in bone marrow biopsy, and the presence of anemia (hemoglobin
9 g/dl). His past medical history was significant for type II diabetes mellitus well
controlled with Metformin and Sitagliptin. On December 30, 2010, he was started on
therapy with single agent bortezomib given at 1.3 mg/m2 intravenously weekly. Dexamethasone was not given due to concern for hyperglycemia
with his underlying diabetes. On January 20, 2011, lenalidomide was added at 10 mg
a day two weeks on and one week off schedule. On February 15, 2011, during approximately
the third cycle of bortezomib treatment, the patient started having severe pain in
both legs extending from his thighs to his calves that he described as “toothache-like”
pain as well as some mild paresthesias and muscle spasms. His chemotherapy was stopped
on March 8, 2011. He also developed progressively worsening bilateral lower extremity
weakness. Within one week, the patient was unable to walk. He could not move his legs
and required the assistance of a wheelchair for mobility.

The patient underwent plasma exchange five times. After the second exchange, he was
able to ambulate with a walker. However, his condition subsequently worsened. On May
31, 2011 prednisone 40 mg PO daily was initiated. Within one to two days after prednisone,
his motor strength started to improve. Two months later, prednisone was gradually
tapered and was completely off on September 9, 2011. At the time of discontinuation
of prednisone, he was able to ambulate with a cane and currently his performance status
is back to his status prior to bortezomib treatment. He is currently in complete remission
from multiple myeloma.

Conclusion

Bortezomib-induced PN occurs mainly in two forms: the first is a direct toxic neuropathy,
which is late onset, much more common, and in general, not as rapidly progressive
and severe. The second form is immune mediated PN [3,7], which is early onset, less common, characterized by prominent motor involvement,
and responds to steroids and intravenous immunoglobulin. Our patient likely developed
the second form of PN (i.e., immune mediated PN). Our patient responds well to plasma
exchange and prednisone, and had nearly complete resolution of his PN.

Currently, there are published guidelines for the management of bortezomib-induced
PN including how to grade PN, when and how to adjust bortezomib dose, and how to use
adjunctive measures [6,8,9]. These guidelines should be followed and all patients who are receiving bortezomib
should be closely monitored for the development of any sensory, motor, or autonomic
neuropathy. In addition, immune therapy such as plasma exchange, IVIG and/or steroid
should be considered if there is evidence of immune-mediated neuropathy such as unexplained
worsening of neurological dysfunction despite bortezomib discontinuation, with prominent
motor involvement, and CSF signs of inflammation [3,7,10]. The overall outcome of bortezomib-related, immune mediated, severe PN is still quite
favorable with the potential of complete resolution of the neuropathy.

Consent

Consents were obtained from the patient for publishing these data.

Competing interests

The authors declared no competing financial interests.

Authors’ contributions

Both Drs. Jeter and Kang participated in the care of the patient and wrote the manuscript.

Authors’ information

Dr. Jeter is a hematology-oncology fellow at the Medical University of South Carolina.
Dr. Kang is an assistant professor and attending physician at the Division of Hematology-Oncology,
Medical University of South Carolina.

Acknowledgements

This work is supported by MUSC Hollings Cancer Center Startup Fund, Hollings Cancer
Center ACS IRG, ASCO Conquer Cancer Foundation Career Development Award, NIH 1K08HL
103780-01A1, and NIH 3P30CA138313-01S3. The content is solely the responsibility of
the authors and does not necessarily represent the official views of the National
Institutes of Health or other funding agents.